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. 2025 Sep 25:e253700.
doi: 10.1001/jamaoncol.2025.3700. Online ahead of print.

Ribociclib Plus Endocrine Therapy in Hormone Receptor-Positive/ERBB2-Negative Early Breast Cancer: 4-Year Outcomes From the NATALEE Randomized Clinical Trial

Peter A Fasching  1 , Daniil Stroyakovskiy  2 , Denise A Yardley  3 , Chiun-Sheng Huang  4 , John Crown  5 , Aditya Bardia  6 , Stephen Chia  7 , Seock-Ah Im  8 , Miguel Martin  9 , Binghe Xu  10 , Sherene Loi  11 , Carlos Barrios  12 , Michael Untch  13 , Rebecca Moroose  14 , Frances Visco  15 , Gabriel N Hortobagyi  16 , Dennis J Slamon  6 , Rodrigo Fresco  17 , Juan Pablo Zarate  18 , Zheng Li  18 , Sorcha Waters  19 , Sara A Hurvitz  20
Affiliations

Ribociclib Plus Endocrine Therapy in Hormone Receptor-Positive/ERBB2-Negative Early Breast Cancer: 4-Year Outcomes From the NATALEE Randomized Clinical Trial

Peter A Fasching et al. JAMA Oncol. .

Abstract

Importance: Ribociclib plus a nonsteroidal aromatase inhibitor (NSAI) has demonstrated a statistically significant invasive disease-free survival (iDFS) benefit over NSAI alone in patients with hormone receptor-positive/ERBB2 (formerly HER2)-negative early breast cancer. Evaluating the efficacy and safety of adjuvant ribociclib beyond the planned 3-year treatment period is critical for understanding the long-term impact on recurrences.

Objective: To evaluate efficacy and safety of adjuvant ribociclib in an exploratory 4-year analysis of the NATALEE (New Adjuvant Trial With Ribociclib [LEE011]) randomized clinical trial, with all patients no longer receiving ribociclib treatment.

Design, setting, and participants: This exploratory analysis of an international, open-label, randomized phase 3 trial analyzed adjuvant treatment for premenopausal and postmenopausal women and men with hormone receptor-positive/ERBB2-negative early breast cancer. Eligible patients had anatomic stage IIA (either N0 with additional risk factors or N1 [1-3 axillary lymph nodes]), IIB, or III disease per the American Joint Committee on Cancer Staging Manual, eighth edition. The data cutoff date was April 29, 2024.

Interventions: Patients were randomized 1:1 to receive ribociclib (400 mg once daily, days 1-21 of a 28-day cycle, over 36 months) plus NSAI (letrozole, 2.5 mg, or anastrozole, 1 mg, once daily continuously for 60 months) or NSAI alone. Men and premenopausal women also received goserelin (3.6 mg once every 28 days administered subcutaneously).

Main outcomes and measures: The primary end point was iDFS, and secondary efficacy end points included distant disease-free survival, recurrence-free survival, and overall survival. Survival was evaluated by the Kaplan-Meier method.

Results: Among 5101 patients included in the analysis (median [range] age, 52 [24-90] years; 5081 [99.6%] female), the median follow-up for iDFS was 44.2 months (range, 0-63 months). Ribociclib plus NSAI continued to show iDFS benefit over NSAI alone (hazard ratio, 0.72; 95% CI, 0.61-0.84), with 3-year iDFS rates of 90.8% vs 88.1% (difference, 2.7 percentage points) and 4-year rates of 88.5% vs 83.6% (difference, 4.9 percentage points). The efficacy benefit was consistent across subgroups and secondary end points. Overall survival data remain immature, although a trend in favor of ribociclib plus NSAI over NSAI alone was observed (hazard ratio, 0.83; 95% CI, 0.64-1.07). The incidence of adverse events has remained stable.

Conclusions and relevance: This exploratory analysis of the NATALEE randomized clinical trial, with a median follow-up beyond the 3-year treatment duration, demonstrated consistent iDFS benefit with ribociclib plus NSAI over NSAI alone.

Trial registration: ClinicalTrials.gov Identifier: NCT03701334.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Fasching reported personal fees from Novartis during the conduct of the study; grants from Cepheid and personal fees from Pfizer, Daiichi Sankyo, AstraZeneca, Eisai, BioNtech, Merck Sharp & Dohme, Lilly, Seagen, Roche, Agendia, Gilead, Mylan, Menarini Stemline, Veracyte, and Guardant Health outside the submitted work; and serving as director of TRIO, which is an uncompensated role. Dr Yardley reported institutional grants from Novartis during the conduct of the study, as well as institutional grants from AbbVie, Ambrx, AstraZeneca, Dana-Farber Cancer Institute, Lilly, Roche/Genentech, G1 Therapeutics, Gilead Sciences, Innocrin Pharmaceuticals, Merck, Polyphor, Stemline Therapeutics, US Oncology, and UT Southwestern, and other institutional support from Arvinas, AstraZeneca, Daiichi Sankyo, Gilead Sciences, Novartis, Pfizer, and Stemline Therapeutics outside the submitted work. Prof Huang reported institutional grants and personal fees from Novartis during the conduct of the study, as well as institutional grants from Daiichi Sankyo, AstraZeneca, EirGenix, Eli Lilly, MSD, OBI Pharma, Pfizer, Roche, Novartis, Seagen, Gilead, and Aston Sci; personal fees from Daiichi Sankyo, AstraZeneca, EirGenix, Eli Lilly, Pfizer, Roche, Novartis, and Gilead; and nonfinancial support from Pfizer, Roche, and Gilead outside the submitted work. Prof Crown reported personal fees from Novartis during the conduct of the study, personal fees from Novartis and Pfizer outside the submitted work, and speakers bureau conference attendance. Prof Bardia reported grants and personal fees from Novartis, Genentech, Merck, Pfizer, Menarini, AstraZeneca, Daiichi Sankyo, Alyssum, and Eli Lilly during the conduct of the study. Dr Chia reported personal fees from Novartis and Eli Lilly during the conduct of the study, as well as personal fees from AstraZeneca, Roche, Daiichi Sankyo, and Exact Sciences outside the submitted work. Dr Im reported grants from Novartis during the conduct of the study, as well as grants from AstraZeneca, Eisai, Daiichi Sankyo, Roche, Daewon Pharm, and Boryung Pharm; personal fees from AstraZeneca, Novartis, Hanmi, Pfizer, Daiichi Sankyo, Eisai, Roche, Lilly, MSD, Bertis, and Idience; and nonfinancial support from GSK outside the submitted work. Dr Martin reported personal fees from Pfizer, Novartis, MSD, Lilly, Bayer, Roche, GSK, and Menarini outside the submitted work. Dr Xu reported personal fees from Novartis and AstraZeneca outside the submitted work. Prof Loi reported institutional research funding from Novartis, Bristol Myers Squibb, Puma Biotechnology, AstraZeneca/Daiichi Sankyo, Roche-Genentech, and Seagen, as well as consulting (compensated and noncompensated) for Roche-Genentech, MSD, Gilead Sciences, AstraZeneca/Daiichi Sankyo, Bristol Myers Squibb, Novartis, Amaroq Therapeutics, Mersana Therapeutics, and Domain Therapeutics outside the submitted work; institutional research funding from Novartis, Bristol Myers Squibb, AstraZeneca/Daiichi Sankyo, Roche-Genentech, MSD, Pfizer, Gilead Sciences, Nektar Therapeutics, and Eli Lilly; and consulting for Roche-Genentech, MSD, Gilead Sciences, AstraZeneca/Daiichi Sankyo, Bristol Myers Squibb, Novartis, Eli Lilly, Amaroq Therapeutics, Mersana Therapeutics, Domain Therapeutics, BioNTech, Bicycle Therapeutics, Exact Sciences, Menarini Asia-Pacific, SAGA Diagnostics, and Adanate. Dr Barrios reported institutional grants from Amgen, AstraZeneca, Aveo Oncology, BioNTech, BMS, Daiichi Sankyo, Dizal Pharma, Exelixis, Fortrea, Gilead Sciences, GSK, ICON, IQVIA, Janssen, Labcorp, Lilly, Medpace, MSD, Novartis, Novocure, Nuvisan, OBI Pharma, Parexel, Pfizer, PharmaMar, PPD, PSI, Regeneron, Roche/Genentech, Samsung, Sandoz, Sanofi, Seagen, Servier, Stemline, Syneos Health, Taiho, Takeda, Tolmar, TRIO, and Worldwide during the conduct of the study, as well as personal fees from Adium, Novartis, Pfizer, Roche/Genentech, MSD, AstraZeneca, Lilly, Daiichi Sankyo, and Gilead outside the submitted work. Prof Untch reported fees to employer/institution from Agendia, AstraZeneca, Daiichi Sankyo, Eisai, Gilead, Lilly, MSD/Merck, Myriad Genetics, Novartis, Pierre Fabre, Pfizer, Roche, Sanofi, Seagen, and Menarini Stemline during the conduct of the study, as well as fees to employer/institution from Agendia, AstraZeneca, Daiichi Sankyo, Eisai, Gilead, Lilly, MSD/Merck, Myriad Genetics, Novartis, Pierre Fabre, Pfizer, Roche, Sanofi, Seagen, and Menarini Stemline outside the submitted work. Dr Hortobagyi reported consulting and serving as a member of a trial steering committee for Novartis outside the submitted work. Dr Slamon reported serving as founder of and stock ownership in TORL BioTherapeutics and 1200 Pharma; serving on the board of directors for, stock ownership in, and travel expenses from BioMarin; grants and research funding from and stock ownership in from Pfizer; consulting and serving on the advisory board for and grants, research funding, and travel expenses from Novartis; consulting for Eli Lilly; and stock ownership in Amgen and Seagen outside the submitted work. Dr Fresco reported institutional contracting with Novartis to conduct the NATALEE trial. Dr Zarate reported personal fees from and stock ownership in Novartis Pharmaceuticals as an employee during the conduct of the study as well as outside the submitted work. Dr Li reported stock ownership in Novartis during the conduct of the study. Dr Waters reported employment and stock ownership in Novartis outside the submitted work. Dr Hurvitz reported nonfinancial support from Novartis for manuscript preparation during the conduct of the study; institutional grants from and serving as an unpaid steering committee member for Arvinas/Pfizer, AstraZeneca/Daiichi Sankyo, Genentech/Roche, Gilead/Immunomedics, Greenwich LifeSciences, Eli Lilly (including Loxo Oncology), Puma, Sanofi, Seagen, Jazz/Zymeworks, Novartis, and Celcuity; institutional grants from Dantari, Roche, G1 Therapeutics, Orinove, Orum, and Radius/Stemline/Menarini; nonfinancial support from Boehringer Ingelheim and MEDSIR as a steering committee member; consulting fees paid to institution from BridgeBio, Daiichi Sankyo, Roche, Mersana, BeOne Medicines, and Blueprint; and personal fees from the Atossa/InClin Data Safety and Monitoring Board outside the submitted work. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Invasive Disease-Free Survival in the Intent-to-Treat Population
The dashed lines at 36 and 48 months represent the planned 3-year treatment duration and 4-year exploratory treatment analysis, respectively. NSAI indicates nonsteroidal aromatase inhibitor.
Figure 2.
Figure 2.. Forest Plot of Invasive Disease-Free Survival (iDFS) Across Clinically Relevant Subgroups
AJCC indicates the American Joint Committee on Cancer Staging Manual, eighth edition; NSAI, nonsteroidal aromatase inhibitor. aFrom archival tumor tissue. bNodal status classification according to AJCC staging. cNodal status is from the worst stage derived per surgical specimen or at diagnosis.
Figure 3.
Figure 3.. Survival Outcomes in the Intent-to-Treat Population
The dashed lines at 36 and 48 months represent the planned 3-year treatment duration and 4-year exploratory treatment analysis, respectively. DDFS indicates distant disease-free survival; DRFS, distant recurrence-free survival; NSAI, nonsteroidal aromatase inhibitor; OS, overall survival; RFS, recurrence-free survival.
See this image and copyright information in PMC

Comment in

  • doi: 10.1001/jamaoncol.2025.3549

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